中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (7): 1505-1511.doi: 10.4103/1673-5374.330613

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

线粒体醛脱氢酶2抑制脊髓损伤后丙烯醛水平

  

  • 出版日期:2022-07-15 发布日期:2022-01-17

Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury

Seth A. Herr1, Liangqin Shi2, Thomas Gianaris3, Yucheng Jiao2, Siyuan Sun1, Nick Race3, Scott Shapiro3, Riyi Shi1, *   

  1. 1Center for Paralysis Research & Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA; 2Department of Orthopedics, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Institute of Trauma and Orthopedics, Shanghai, China; 3Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
  • Online:2022-07-15 Published:2022-01-17
  • Contact: Riyi Shi, MD, PhD, riyi@purdue.edu.
  • Supported by:
    The study was supported by a grant from National Institute of Neurological Disorders and Stroke R21 (No. 1R21NS115094-01).

摘要:

脂质过氧化产生的醛,如丙烯醛在脊髓损伤(SCI)后继发性损伤致功能丧失中有关键作用。有证据表明,线粒体醛脱氢酶2(ALDH2)是一种关键的氧化还原酶和强大的内源性抗醛机制,对抵抗醛类物质介导 的神经元退化有重要作用。实验利用脊髓挫伤大鼠模型,验证了ALDH2激活剂Alda-1的清除醛类和神经保护作用。在脊髓损伤后2天的急性期,实验发现ALDH2的表达在脊髓损伤后明显降低,但在给予Alda-1的大鼠中却不是这样。实验还发现,给予脊髓损伤大鼠Alda-1干预后,脊髓中的丙烯醛水平明显降低,并减少了囊肿病变。此外,直至脊髓损伤后28天Alda-1干预也使脊髓挫伤大鼠运动功能明显改善,并减轻了脊髓损伤后的中枢性疼痛。最后发现ALDH2在体外保护PC12细胞免受丙烯醛暴露的影响方面发挥了关键作用。此项研究结果将为对抗脊髓损伤后继发性神经损害的抗醛策略的制定提供基础。

https://orcid.org/0000-0002-7297-9428 (Riyi Shi)

Abstract: Lipid peroxidation-derived aldehydes, such as acrolein, the most reactive aldehyde, have emerged as key culprits in sustaining post-spinal cord injury (SCI) secondary pathologies leading to functional loss. Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2 (ALDH2), a key oxidoreductase and powerful endogenous anti-aldehyde machinery, is likely important for protecting neurons from aldehydes-mediated degeneration. Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator (Alda-1), we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2. Over an acute 2 day period post injury, we found that ALDH2 expression was significantly lowered post-SCI, but not so in rats given Alda-1. This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction, which was revealed in co-immunoprecipitation experiments. We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord, and reduced cyst pathology. In addition, Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI. Finally, ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure. It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims. All animal work was approved by Purdue Animal Care and Use Committee (approval No. 1111000095) on January 1, 2021.

Key words: acrolein, acrolein-lysine adduct, alda-1, enzymatic catalyst, lipid peroxidation, mitochondrial aldehyde dehydrogenase-2, neurotrauma, oxidative stress, reactive aldehydes, spinal cord contusion